JP2023029328A - High-performance microneedle array 2 - Google Patents

Abstract

To provide a microneedle array with high bioavailability and high pharmacological availability.SOLUTION: The microneedle array comprises a needle part 4 and a substrate part 3. The needle part contains a valuable material in a base that has a water-soluble polymer as a main component. The substrate part does not contain any valuable material, and a base of the substrate part has a non-water-soluble polymer as a main component.SELECTED DRAWING: Figure 1

Description

The present invention relates to high performance microneedle arrays. Specifically, it relates to the technical field of microneedles that achieve high absorption of valuable substances and pharmacological effects.

Microneedles have been extensively studied as a method for reliably supplying medicinal ingredients to specific locations in the skin surface layer and/or the stratum corneum. For example, in conventional self-dissolving microneedles, the target substance is dissolved or dispersed throughout the needle, or dissolved or dispersed at the tip of the needle. When the valuable substance is expensive, if the valuable substance is contained in the entire microneedle array, the valuable substance contained in the substrate portion of the microneedle array is wasted, so the valuable substance is contained only in the tip of the microneedles. There is a need. The base for dissolving or dispersing the target substance is composed of a water-soluble polymer substance, and for example, polysaccharides, proteins, polyvinyl alcohol, carboxyvinyl polymer, polyvinylpyrrolidone, copolymers thereof, and salts thereof are used. It has been. The substrate portion on which the needles stand does not contain the target substance, but the same water-soluble polymer as the base constituting the needle portion has been used (for example, Patent Documents 1 and 2).

Japanese Patent No. 5538897 JP 2017-051312 A

For the microneedle array, microneedles with a total length of about 150 to 1500 μm have been preferably used from the viewpoint of ease of handling (for example, ease of insertion into the skin). However, when a microneedle of this size is applied to the skin using an applicator, the whole needle part is inserted into the skin, the water-soluble polymer base dissolves in the skin, and the target substance migrates to the skin. do. At that time, it was observed that the target substance existing at the rear end portion of the needle part diffused into the skin and at the same time diffused into the substrate part. As a result, part of the target substance contained in the needle part does not diffuse into the skin and moves to the substrate part, and since the substrate part is removed from the skin after microneedle administration, it is virtually not absorbed into the body. was discarded as is. This loss has been found to be one obstacle to improved bioavailability and pharmacological availability.
The problem to be solved by the present invention is to provide a microneedle array with high bioavailability and pharmacological availability.

In particular, when the target substance is an expensive proteinaceous drug, even a small amount of loss poses a serious problem in commercialization. Accordingly, the present inventors have advanced research to solve this problem, and have completed the invention described in detail below.
The present invention is as described below.
[1] In a microneedle array composed of a needle portion and a substrate portion, the needle portion contains a valuable substance in a base mainly composed of a water-soluble polymer, and the substrate portion does not contain a valuable substance. First, a microneedle array characterized in that the base material of the substrate portion contains a water-insoluble polymer as a main component.
[2] The microneedle array according to [1], wherein the SP value of the water-insoluble polymer of the substrate portion is 9.0 or more.
[3] The micrometer according to [1] or [2], wherein the difference between the SP value of the water-soluble polymer in the needle portion and the SP value of the water-insoluble polymer in the substrate portion is 4 or less. needle array.
[4] The needle portion has a length of 0.02 to 1.5 mm, and has a conical shape, a truncated conical shape, a triangular or polygonal pyramid shape, or a triangular or polygonal truncated pyramid shape [1]- The microneedle array according to any one of [3].
[5] The microneedle array according to any one of [1] to [4], wherein the substrate has a thickness of 0.01 to 1.0 mm.
[6] The water-insoluble polymer is one or more selected from the group consisting of cellulose acetate, epoxy resin, maleic anhydride-methyl vinyl ether copolymer, and acrylic acid-acrylic acid ester copolymer. The microneedle array according to any one of [1] to [5].
[7] The tip portion of the needle portion contains a valuable substance, and the base portion of the needle portion does not contain a valuable substance and is composed of a base mainly composed of a water-insoluble polymer, [1] to The microneedle array according to any one of [6].
[8] It is characterized in that the length of the base portion which does not contain the valuable substance and is composed of the base mainly composed of the water-insoluble polymer is 60% or less of the needle length of the entire needle portion. The microneedle array according to [7].
[9] A method for producing a microneedle array according to any one of [1] to [8], comprising the following steps:
1) preparing a mold having a concave microneedle pattern by lithography or precision metalworking;
2) a step of applying an aqueous solution containing a valuable substance and a base water-soluble polymer to the surface of the mold and drying it;
3) a step of applying a base solution composed of an organic solvent containing a water-insoluble polymer as a base to the surface of the mold after the drying step, and drying;
4) A manufacturing method including a step of removing the formed microneedle array from the mold.

According to the present invention, in order to minimize the loss of the target substance, the base of the substrate portion is mainly composed of a water-insoluble polymer, so that the substrate portion does not swell even when the formulation is administered. It is possible to prevent the target substance from diffusing into the substrate portion. As a result, higher absorption rate and pharmacological effect of the target substance can be achieved.

BRIEF DESCRIPTION OF THE DRAWINGS Sectional drawing which shows an example of the microneedle array of this invention. Sectional drawing which shows another example of the microneedle array of this invention. Micrographs of microneedle arrays of type 1 (Examples 3 and 4). Photomicrographs of microneedle arrays of type 2 (comparative examples 3 and 4). A micrograph of a microneedle array of type 3 (comparative example 5).

The microneedle array of the present invention has a base made of a substance soluble in the body and a target substance held in the base, is used by inserting into the skin, and dissolves the base to obtain the target substance. A needle-shaped preparation that is absorbed into the body, in which the target substance is retained in the entire needle or at the tip, and the target substance is obtained by solidifying the base in which the target substance is dissolved or dispersed. dissolved or dispersed in The feature of the present invention resides in that the substrate portion which does not have the target substance is made of a base containing a water-insoluble polymer as a main component instead of a water-soluble polymer.

The formulation for skin application of this aspect has a needle-like shape and is used by inserting it into the body surface such as the skin. become. First, a conventional case where the needle portion and the substrate portion are made of a water-soluble substance will be described. The target substance is absorbed into the body by dissolving the base, but the tip is deep in the skin and has a lot of water in the tissue, so the base quickly swells and dissolves in the tissue, and the target substance is absorbed accordingly. diffuses into the skin. When the needle is inserted into the skin, the rear end of the needle is close to the skin surface and swells due to exudate from the inside of the skin, but the water passes through the rear end of the needle and diffuses to the substrate, causing the substrate to swell. The target substance dissolved at the rear end of the needle acquires mobility as the base of the needle swells, and diffuses into the skin as well as into the swollen substrate. The target substance diffused to the substrate part does not effectively act on the skin, resulting in loss of the target substance.

In order to minimize the loss of the target substance, if the substrate is made water-insoluble, the substrate will not swell even when the formulation is administered, and thus the target substance can be prevented from diffusing into the substrate. . As a result, higher absorption rate and pharmacological effect of the target substance can be achieved.

It is not preferable that the base polymer of the needle part and the base part is water-soluble in the former and water-insoluble in the latter from the viewpoint of mutual compatibility between different polymers in terms of formulation. Different polymers generally have poor compatibility, thus compromising the mechanical strength of the microneedle array. As a result of studies by the present inventors, in order to maintain the affinity between the needle portion polymer and the substrate portion polymer, if the difference in solubility parameter value (hereinafter referred to as SP value) between the two polymers is 4 or less, , it has been found that it retains sufficient mechanical strength for practical use. The difference in SP value is usually 5 or less, preferably 4 or less.
The SP value was advocated in the 1950s and is still widely used as a parameter for quantifying the polarity of high and low molecular weight molecules. be done. There are various documents on methods for estimating the SP value from the structural formula of the molecule. For example, Shinichi Ueda et al., Research on Paint No. 152, P. 41-46 Oct. 2010 can be used as a reference. The SP value of the object is calculated with reference to these documents. Regarding the SP value of the polymer, the SP value of the repeating unit is taken as the SP value of the polymer. The SP value of the copolymer is defined as the mass ratio of the monomers constituting the copolymer.

The main component of the needle base is a water-soluble polymer. Examples of water-soluble polymers include proteins such as collagen (or hydrolyzed collagen) and gelatin; polysaccharides such as hyaluronic acid, dextrin, dextran, proteoglycan, sodium chondroitin sulfate; and polymers such as carboxymethylcellulose and hydroxyethylcellulose. be done. All of these have SP values of 14.0 or more. In addition, from the group consisting of synthetic polymers such as polyvinyl alcohol (12.6), carboxyvinyl polymer (14.0), polyvinylpyrrolidone (14.9), and copolymers thereof and salts thereof At least one selected can be used. Numerical values in ( ) are SP values.
The main component of the needle base may be a water-soluble polymer for all of the components of the base, and may include other components as long as the needle swells and dissolves after skin administration. , the content of the water-soluble polymer may be less than 100% by mass in the base.

The base of the needle part of the microneedle array can contain a water-soluble low-molecular-weight compound in addition to the water-soluble polymer. Examples of water-soluble low-molecular-weight compounds include monosaccharides, disaccharides, and polyhydric alcohols having a molecular weight of 500 or less. Monosaccharides include glucose, fructose and the like, and disaccharides include sucrose, lactose, trehalose, maltose and the like. Polyhydric alcohols include glycerin, propylene glycol (PG), butylene glycol (BG), polyethylene glycol (PEG) 200, PEG400 and the like. One or more of these can be used.
The amount of the water-soluble low-molecular-weight compound added is 2% by mass or more and less than 50% by mass, preferably 2% by mass or more and 35% by mass or less as the concentration in the base.

A high SP value is also required for the water-insoluble polymer of the substrate part base material, which requires affinity with the water-soluble polymer. Specifically, ethyl cellulose (10.3), cellulose acetate (11.0), epoxy resin (11.2), maleic anhydride-methyl vinyl ether copolymer (10.0), acrylic acid-acrylate copolymer At least one selected from the group consisting of polymers (8.7 to 11.8) and polycyanoacrylates (10.7) can be used. Many water-soluble polymers have an SP value of 12.6 or more, and considering the affinity with them, the SP value of the water-insoluble polymer of the substrate part base is 9.0 or more. is preferable, and 9.5 or more is more preferable.
As described above, the water-soluble polymer and the water-insoluble polymer of the substrate portion base require high affinity and high adhesiveness based thereon. If the adhesiveness at the interface between the two polymers is weak, the interface will peel off due to the impact when the microneedle is injected into the skin after molding, and the microneedle will break, making the insertion of the needle into the skin unstable. The strength of the adhesive strength at the interface can be quantitatively evaluated by measuring the rupture or peeling behavior of the microneedles by measuring the compressive strength of the molded microneedles.
The main component of the base of the base may be all water-insoluble polymers, and may contain other components as long as the base does not swell or dissolve after being administered to the skin. , the content of the water-insoluble polymer may be less than 100% by mass in the base.

The microneedle array of the present invention may contain valuable substances such as cosmetic raw materials or medicinal ingredients, particularly macromolecular medicinal ingredients. A suitable content of the valuable substance is 0.001% by mass to 30% by mass with respect to the mass of the needle portion.

Raw materials for the above cosmetics include, for example, whitening ingredients such as ascorbyl palmitate, kojic acid, rucinol, tranexamic acid, oily licorice extract, vitamin A derivatives, placenta extract, magnesium adenosine sulfate; retinol, retinoic acid, and retinol acetate. , retinol palmitate, EGF, cell culture extract, adenosine, etc.; anti-wrinkle ingredients; α-tocopherol, tocopherol acetate, capsaicin, vanillylamide nonylate, etc.; blood circulation promoting ingredients; raspberry ketone, evening primrose extract, seaweed extract, etc.; antibacterial ingredients such as methylphenol, photosensitizer, zinc oxide; vitamins such as vitamin D ₂ , vitamin D ₃ and vitamin K;

Examples of the macromolecular active ingredients include physiologically active peptides and derivatives thereof, nucleic acids, oligonucleotides, various antigenic proteins for use in vaccines, bacteria, virus fragments, antibodies, and the like.

Examples of the physiologically active peptides and their derivatives include calcitonin, adrenocorticotropic hormone, parathyroid hormone (PTH), hPTH (1→34), insulin, exendin and its derivatives, secretin, oxytocin, angiotensin, β- Endorphin, glucagon, vasopressin, somatostatin, gastrin, luteinizing hormone-releasing hormone, enkephalin, neurotensin, atrial natriuretic peptide, growth hormone, growth hormone-releasing hormone, FGF, bradykinin, substance P, dynorphin, erythropoietin, thyroid stimulating hormone , prolactin, interferon, interleukin, G-CSF, glutathione peroxidase, superoxide dismutase, desmopressin, somatomedin, endothelin, and salts thereof. Examples of antigen proteins include influenza virus antigen, HBs surface antigen, and HBe antigen, and examples of antibodies include various polyclonal antibodies and monoclonal antibodies that are used as antibody drugs.

The microneedle array of the present invention is composed of a needle portion and a substrate portion.
The needle is 0.02-1.5 mm long, preferably 0.1-1.0 mm. The shape of the needle includes a conical shape, a truncated conical shape, a triangular or polypyramidal shape, or a triangular or polypyramidal truncated shape.

The substrate portion has a thickness of 0.01 to 1.0 mm, preferably 0.05 to 0.4 mm.

The microneedle array of the present invention contains a valuable substance in the needles, but may contain the valuable substance in the tip of the needles and may not contain the valuable substance in the base of the needles. In that case, it is desirable that the root portion of the needle portion is made of a base material containing a water-insoluble polymer as a main component. As the water-insoluble polymer, the same water-insoluble polymer as used for the base of the substrate portion can be used.

When the needle part of the microneedle array of the present invention is composed of a tip part and a root part (see, for example, FIG. 2), the length of the tip part is 0.01 to 1.4 mm, and 0.1 ~1.2 mm is preferred. The length of the root portion is 60% or less of the needle length of the entire needle portion, and is 0.05 to 0.7 mm, preferably 0.1 to 0.3 mm.

Microneedle Array Manufacturing Method The microneedle array manufacturing method of the present invention includes the following steps 1) to 4).
1) Step of preparing a mold having a concave microneedle pattern by a lithography method or a precision metal processing method As the lithography method and the precision metal processing method, methods known in the art can be used.
2) A process of applying an aqueous solution containing a valuable substance and a base water-soluble polymer to the surface of the mold and drying it. It is valid. Scrape off the semi-solids on the mold surface before the coating liquid dries sufficiently. When the surface of the mold is scraped off with the coating liquid almost dry, the proportion of needles containing valuable substances is large, and when the drying time of the coating liquid is short, the proportion of needles containing valuable substances in the finished microneedles is small. It becomes a microneedle array.
3) A step of applying a base solution composed of an organic solvent containing a water-insoluble polymer as a base to the surface of the mold after the drying step, and drying the solution.
4) Step of removing the formed microneedle array from the mold

The present invention will now be described in more detail with reference to the following examples. These examples are merely examples for specifically describing the present invention, and the scope of the present invention is not limited to these examples.

Manufacture of the mold In manufacturing the microneedle array, first, a microneedle pattern of a predetermined shape is formed by a lithography method in which a photosensitive resin is irradiated with light, and then the microneedle pattern of a predetermined shape is transferred by electroforming. A mold with recesses was produced.
The microneedle-forming recesses of this mold have a conical shape with an inlet diameter of 0.2 to 0.5 mm, a bottom diameter of 0.02 to 0.1 mm, and a depth of 0.02 to 1.5 mm. They are arranged in a lattice at intervals of ~1.0 mm. The area was a square of 10x10 cm.
An example of the cross-sectional shape of the microneedle array formed by this template is shown in FIG. Each microneedle has a truncated cone shape with a base diameter (b) of 0.3 mm, a needle tip diameter (c) of 0.04 mm, and a needle length (a) of 0.8 mm. ) are arranged in a grid. When this microneedle array is formed in a circle, it contains about 250 needle portions 4 in 1 cm ² . The substrate portion 3 is made of a polymer different from that of the needle portion 4, and its thickness (e) is 0.4 mm. The microneedle array of this shape is hereinafter referred to as 800-MN.
Another example of the cross-sectional shape of the microneedle array formed by this template is shown in FIG. The shape of each microneedle is the same as that of the microneedle array in FIG. 1, but the root portion of the needle portion 4 in FIG. The distal end portion and the root portion of the needle portion are made of different polymers. The length of the tip of the needle containing valuables is shorter than 0.8 mm.

Preparation of Microneedle Array Using the prepared template, 800-MN microneedle arrays of Examples 1 and 2 and Comparative Examples 1 and 2 having the compositions shown in Table 1 were prepared.
An 800-MN molding die was used to mold the needle. The needle part valuables and base composition shown in Table 1 are blended, the solution is cast on an 800-MN mold, dried under a pressure of 1.0 KPa for 1 hour and removed, and the semi-solid on the mold surface is removed. Removed by scraping. A concentrated aqueous solution of the base containing the valuable substance remained in the depressions. After that, the base polymer solution for the substrate portion was poured onto the substrate portion so that the thickness after drying was 0.4 mm, and dried under a pressure of 1.0 KPa for 12 hours. The microneedle array formed on the mold surface was peeled off from the mold, and the microneedle array was punched out into a circle with a diameter of 10 mm to obtain a microneedle patch. The zolmitriptan content in Example 2 and Comparative Example 1 was about 450 μg as determined from the drug concentration measured by extracting valuable substances from the prepared microneedle patch.
As a reference example, 450 µg of zolmitriptan was also subcutaneously injected, and the blood concentration was measured by blood sampling over time.

Evaluation (1) Moldability Microneedle patches prepared were observed under a microscope to evaluate needle moldability.
(2) Performance Evaluation A microneedle patch containing zolmitriptan as a valuable substance (Example 2 and Comparative Example 1) was administered to Wistar rats (6 to 8 weeks old) via an applicator in the abdomen, and removed after 30 minutes. Blood was collected at 0 (before administration), 15, 30, 60, 120, 180, 300, and 420 minutes, the blood concentration of zolmitriptan was measured, the blood concentration-time curve was obtained, and bioavailability (BA) was determined. Calculated. For comparison, blood concentration-time curves were also obtained for subcutaneous injection administration and oral administration. All tests were N=3, and the average value was obtained.

Results The results are shown in Table 2.

The reason why the BA value is low in Comparative Example 1 is that the target substance dissolved at the needle rear end part gains mobility and diffuses into the skin as it swells due to the body moisture of the needle base and the substrate base, and swells at the same time. It is thought that this is due to diffusion to the substrate portion where the As a result of separately extracting and quantifying the drug transferred to the substrate, it was 28%.
In Comparative Example 2, there was a large difference in polarity between the polymer of the base of the needle portion and the polymer of the base portion of the substrate, and the compatibility was low. be.

Preparation of microneedle array 2
In fabricating a microneedle array, first, a microneedle pattern of a predetermined shape is formed by a lithography method that irradiates a photosensitive resin with light, and then a concave portion for microneedle formation is formed by transferring the microneedle pattern of a predetermined shape by electroforming. A molded mold was manufactured.
The microneedle-forming recesses of this mold have a conical shape with an inlet diameter of 0.2 to 0.5 mm, a bottom diameter of 0.02 to 0.1 mm, and a depth of 0.02 to 1.5 mm. They are arranged in a lattice at intervals of ~1.0 mm. The area was a square of 10x10 cm.
In this experiment, a needle length of 0.9 mm, a needle interval of 0.75 mm, a needle base diameter of 0.3 mm, and a plastic mold having a conical needle shape were used.
Polyvinyl alcohol or hyaluronic acid aqueous solution containing 0.05% by mass of a red dye (New coccine, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) was filled into the cavities of the mold and dried. After drying, the mold was filled with various polymers forming the substrate portion in the form of water or organic solvent solutions, and then centrifuged for 20 minutes to integrate with the needle portion. Then, it was dried for 12 hours, the microneedle array was taken out from the mold, and the state of the microneedle array was observed under a microscope. Table 3 shows the properties of the fabricated microneedle arrays (Examples 3 and 4 and Comparative Examples 3-5).

Different microneedle arrays were produced using various substrate polymers, and they were roughly classified into the following three types.

type 1
As shown in FIG. 3, the needle portion and the substrate portion are completely integrated. The dye in the needle remains in the needle without diffusing into the substrate. The gist of the present invention is realized.

type 2
As shown in FIG. 4, the needle portion and the substrate portion are completely integrated. However, the dye in the needle portion diffuses to the substrate portion. In this case, if the drug filled in the needles is water-soluble, the drug will diffuse into the substrate formed from the water-soluble polymer during the drying process of the microneedle array, resulting in a drug concentration in the needles of is inconvenient because it decreases.

type 3
As shown in FIG. 5, when the microneedle array is removed from the mold, the needles remain in the mold and are not completely integrated with the substrate (left half in FIG. 5). This is because there is a large difference in polarity between the polymers of the needle portion and the substrate portion, and the affinity between the two is small.

3 substrate part 4 needle part

Claims (9)

In a microneedle array composed of a needle portion and a substrate portion, the needle portion contains a valuable substance in a base mainly composed of a water-soluble polymer, and the substrate portion does not contain a valuable substance. A microneedle array, wherein the base material of the substrate part contains a water-insoluble polymer as a main component. The microneedle array according to claim 1, wherein the SP value of the water-insoluble polymer of the substrate portion is 9.0 or more. 3. The microneedle array according to claim 1, wherein the difference between the SP value of the water-soluble polymer of the needle portion and the SP value of the water-insoluble polymer of the substrate portion is 4 or less. 4. The needle part has a length of 0.02 to 1.5 mm, and is conical, truncated conical, triangular or polypyramidal, or triangular or truncated polypyramidal. or the microneedle array according to item 1. The microneedle array according to any one of claims 1 to 4, wherein the substrate has a thickness of 0.01 to 1.0 mm. wherein the water-insoluble polymer is one or more selected from the group consisting of cellulose acetate, epoxy resin, maleic anhydride-methyl vinyl ether copolymer, and acrylic acid-acrylic acid ester copolymer; The microneedle array according to any one of items 1 to 5. 7. Any one of claims 1 to 6, wherein the tip portion of the needle portion contains a valuable substance, and the base portion of the needle portion does not contain a valuable substance and is composed of a base mainly composed of a water-insoluble polymer. or the microneedle array according to item 1. The length of the root portion composed of the base material containing no valuable substance and containing a water-insoluble polymer as a main component is 60% or less of the needle length of the entire needle portion. Item 8. The microneedle array according to item 7. A method for producing a microneedle array according to any one of claims 1 to 8, comprising the following steps:
1) preparing a mold having a concave microneedle pattern by lithography or precision metalworking;
2) a step of applying an aqueous solution containing a valuable substance and a base water-soluble polymer to the surface of the mold and drying it;
3) a step of applying a base solution composed of an organic solvent containing a water-insoluble polymer as a base to the surface of the mold after the drying step, and drying;
4) A manufacturing method including a step of removing the formed microneedle array from the mold.

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